A series of short peptides with significant activity as cell growth inhibitors have been isolated from the Indian Ocean sea hare Dolabella auricularia (Pettit et al., J. Am. Chem. Soc. 109: 6883-6885 (1987); Beckwith et al., J. Natl. Cancer. Inst. 85: 483-88 (1993); U.S. Pat. No. 4,816,444; European Patent Application Publication No. 398,558). These peptides are referred to as Dolastatins 1-15. Of these, Dolastatins 10 and 15 are the most potent cell growth inhibitors. Dolastatin 15, for example, inhibits the growth of the National Cancer Institute's P388 lymphocytic leukemia (PS system) cell line, a strong predictor of efficacy against various types of human malignancies. Dolastatin 10 and Dolastatin 15 effectively inhibit tubulin polymerization and growth of four different human lymphoma cell lines (Bai et al., Biochem. Pharmacol. 39: 1941-1949 (1990); Beckwith et al., supra (1993)).
The minute amounts of the Dolastatin peptides present in Dolabella auricularia (about 1 mg each per 100 kg sea hare) and the consequent difficulties in purifying amounts sufficient for evaluation and use, have motivated efforts toward the synthesis of the more promising of these compounds, including Dolastatin 10 (Pettit et al., J. Am. Chem Soc. 111: 5463-5465 (1989); Roux et al. Tetrahedron 50: 5345-5360 (1994); Shiori et al. Tetrahedron 49: 1913-1924 (1993)). Synthetic Dolastatin 10, however, suffers from disadvantages which include poor solubility in aqueous systems and the need for expensive starting materials for its synthesis. These disadvantages, in turn, have led to the synthesis and evaluation of structurally modified Dolastatin 10 derivatives (European Patent Application, Publication No. WO 93/03054; Japanese Patent Application No. 06,234,790; U.S. Pat. No. 5,502,032.
A need persists for synthetic compounds with the biological activity of Dolastatin 10 which have useful aqueous solubility and can be produced efficiently and economically.